Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China.
Precision Scientific (Beijing) Ltd., Beijing 100085, China.
Sci Adv. 2020 Feb 26;6(9):eaay4211. doi: 10.1126/sciadv.aay4211. eCollection 2020 Feb.
Neoadjuvant chemotherapy is a common treatment for patients with gastric cancer. Although its benefits have been demonstrated, neoadjuvant chemotherapy is underutilized in gastric cancer management, because of the lack of biomarkers for patient selection and a limited understanding of resistance mechanisms. Here, we performed whole-genome, whole-exome, and RNA sequencing on 84 clinical samples (including matched pre- and posttreatment tumors) from 35 patients whose responses to neoadjuvant chemotherapy were rigorously defined. We observed increased microsatellite instability and mutation burden in nonresponse tumors. Through comparisons of response versus nonresponse tumors and pre- versus posttreatment samples, we found that mutations were associated with treatment resistance, which was supported by drug response data and potentially through inhibition of cell cycle, and that amplification correlated with treatment sensitivity, whereas amplification showed the opposite pattern. Neoadjuvant chemotherapy also reshapes tumor-immune signaling and microenvironment. Our study provides a critical basis for developing precision neoadjuvant regimens.
新辅助化疗是胃癌患者的常用治疗方法。尽管其益处已得到证实，但由于缺乏用于患者选择的生物标志物和对耐药机制的认识有限，新辅助化疗在胃癌治疗中的应用不足。在这里，我们对 35 名患者的 84 个临床样本（包括配对的治疗前和治疗后肿瘤）进行了全基因组、全外显子组和 RNA 测序，这些患者的新辅助化疗反应经过严格定义。我们观察到无反应肿瘤中微卫星不稳定性和突变负担增加。通过对反应性与非反应性肿瘤以及治疗前与治疗后样本的比较，我们发现 突变与治疗耐药性相关，这一结果得到了药物反应数据的支持，并且可能是通过抑制细胞周期实现的，而 扩增与治疗敏感性相关，而 扩增则呈现相反的模式。新辅助化疗还重塑了肿瘤免疫信号和微环境。我们的研究为开发精准的新辅助方案提供了重要基础。
